Our experimental collaborators in the Cushman lab (NIDDK) have been using improved technology for measuring fat cell size to attempt to discern relationships between fat cell size and insulin resistance. One motivation for this is that obesity is associated with large fat cells and with insulin resistance, so it has been proposed that large fat cells are intrinsically insulin resistant and therefore cause insulin resistance. The studies of Cushman have shown that the situation is a good deal more complicated. For one thing, it is misleading to describe fat cell size with a single (mean) value for diameter or volume, because the distribution of cell sizes is not Gaussian. Rather, there is a tail of small cells in addition to the previously observed peak of large cells, and the mean typically falls between these two concentrations of cells. We therefore investigated whether the details of the distribution carry information about tissue function by comparing the cell-size histograms from weight-matched human subjects who were either insulin sensitive (IS) or insulin resistant (IR). We carried out a data reduction by fitting the cell-size histograms to a function with seven parameters, describing a bell-shaped peak for the large cells plus two exponentials for the tail of small cells. We found that the size of the large cells did not differ much between IS and IR subjects, but that the proportion of large cells was smaller in the IR group. We thus developed the new hypothesis that IR is associated with a defect in adipocyte development that prevents either recruitment of new small fat cells or their final differentiation to mature, large fat cells. This could cause insulin resistance by limiting the capacity of the fat tissue to store fat, resulting in ectopic fat deposition in other tissues, such as muscle, liver, and pancreas. The results are presented in Ref. # 1. Further work in progress has gone on to examine cell-size distributions in response to other changes that affect insulin resistance, such as weight loss and treatment with insulin-sensitizing drugs (thiozolidene diones or TZDs). The preliminary results of these studies are compatible with the hypothesis that fat storage capacity, not fat cell size per se, is the more central determinant of insulin signaling.